Pigment tied to blindness, cancer:

For a long time, scientists have wondered why blacks seldom get skin cancer or macular degeneration, the major cause of blindness in elderly white people. Experiments at the Children’s Hospital in Boston have yielded one possible answer – the black pigment called melanin apparently protects them in a peculiar way.

Melanin blocks the growth of blood vessels, an oversupply of which leads to blindness. “Wherever melanin is, blood vessels don’t like to go,” says Robert D’Amato, an associate professor of ophthalmology at Harvard Medical School who led the experiments at Children’s Hospital.

D’Amato’s team exposed two strains of mice to growth factors, proteins that stimulate growth of blood vessels. Those that lacked pigment in their irises, the area surrounding the pupil, experienced abundant blood vessel growth. Mice with black eyes did not.

“We see the same thing in black patients with macular degeneration,” D’Amato notes. People of all races can develop the dry form of macular degeneration, which involves small yellow spots that don’t affect vision too much. But in nonblacks, blood vessels grow behind the retina and severely damage vision, blocking out the center of the field of sight, or producing blindness. In black people the disease seldom progresses that far.

One obvious treatment would be to give white people black eyes. “We’re thinking about ways to do this, to find a way to stimulate melanin growth in the eyes of Caucasians at risk for macular degeneration,” D’Amato says. “About a dozen genes regulate pigmentation, and we are studying the influence of these genes. If we can use this information to boost pigmentation it could help protect the sight of many people.”

One side effect would make your blue eyes black, or at least darker. “You would definitely see a change in color toward black,” D’Amato admits, “but I don’t know how pronounced that would be.”

Cutting the blood supply

People may be willing to change their eye color to save their sight, but what about changing skin color to protect against skin cancer?

Blacks don’t get as sunburned as whites. “The conventional thinking is that melanin in their skin blocks the ultraviolet radiation that can lead to cancer in other races,” D’Amato points out. “But I think that an equally important deterrent could be the fact that melanin stops the growth of new blood vessels.” Without new blood vessels to bring them nutrients, tumors cannot survive.

Although there are ways to stimulate melanin production in skin, D’Amato does not believe this will ever catch on as a prophylactic against melanoma. “You would have to keep using it continuously and I doubt anyone would want to do that,” he says. You can get all the protection you need by staying out of the sun or using a sunscreen and clothing to protect yourself.

Treating macular degeneration is another story, however. D’Amato led the first research to determine that the growth of blood vessels could be arrested with the drug thalidomide. That drug had a horrific reputation at one time. Hundreds of women in England, Europe, and Japan took it as a sedative when they were pregnant and gave birth to children with shortened arms and legs.

For 30 years no one could figure how this sedative could cause such terrible malformation. D’Amato was able to show that thalidomide interfered with growth of blood vessels necessary for the development of limbs in embryos two to three week old. This led him to the idea that the drug might be modified to prevent the growth of blood vessels responsible not only for macular degeneration, but diabetic retinopathy, which blinds people with diabetes. Together they are the two major causes of blindness in the United States and many other countries.

Since that discovery in 1994, D’Amato and his colleagues have been modifying thalidomide in ways to reduce its sedative side effects and increase its potency with the aim of using it to prevent blindness.

It’s not the tumor’s fault

D’Amato’s laboratory is on the same floor as that of Judah Folkman, who first found that the cancer tumors cannot grow without a blood supply. Autopsies show that the majority of people who die of natural causes have small dormant tumors in their bodies. If these potential malignancies don’t trigger the growth of new blood vessels, a person dies with cancer but not of it.

This research has led to the development of approximately 50 drugs, including thalidomide, to inhibit blood-vessel development. So far, the use of thalidomide and other drugs derived from it shows great promise for treatment of multiple myeloma (bone marrow cancer), as well as kidney cancer and melanoma. But some blood-vessel inhibitors used on a variety of other cancers have not been as successful as Folkman, D’Amato, and many others hoped they would be.

One of the stubborn mysteries of treating cancers is the resistance of some tumors to treatment. If you have two women of the same age and medical background with the same size breast tumor, the outcomes of using the same drug can be completely different. One woman will be free of active cancer 10 years later, while the cancer of the other will spread and lead to an early death.

“The conventional explanation is that it’s the tumors’ fault,” D’Amato notes. “Everyone thought that some tumors are naturally more aggressive than others. In our experiments with mice, we took an opposite view. The answer might lie in a person’s natural ability to resist the growth of blood vessels, or to permit their rapid development. We asked ourselves, is it the host rather than the tumor?”

At first, D’Amato and his team thought that couldn’t be true because blood vessels are so important for growth, especially in the womb. “It’s something everyone needs in his or her life,” he notes. “So if there is any difference between hosts, it must be small. But when we tested different strains of mice to check this out, we found that some strains have five, even 10, times greater ability to grow new blood vessels than others.” His laboratory is now working to find and isolate the numerous genes that control blood vessel growth.

Does this mean that your genes, rather than your tumors, determine if you will survive cancer or not? Environmental factors such as diet, smoking, and pollution must also play a role. Despite that, however, some people may have a greater tendency than others to produce growth factors that stimulate proliferation of new blood vessels and aid the energetic spread of cancer. If so, drugs might be developed to suppress such activity.

But D’Amato doesn’t think that will be a simple task. Those with a genetic tendency to aggressively grow new blood vessels could be more resistant to such drugs. Also, these new medicines often target only one pathway in the complex process of growing a blood supply. “If you treat a tumor that doesn’t produce the specific growth factor targeted by your drug, you’ll get no response,” D’Amato points out. “If the tumor makes a particular growth factor and you block it, the tumor may mutate to make another factor that will allow it to keep growing.”

Nevertheless, D’Amato’s genetic studies of mice present a novel view of the treatment of cancers and the major causes of blindness. He and his colleagues have already discovered that the genes involved in pigmentation offer some protection. It is only a matter of time before other genes will be found and used to determine whether an individual grows blood vessels rapidly.

D’Amato envisions a simple skin test to separate fast vessel growers from slow ones. A little growth factor injected under the skin might show which one of two women with the same-size breast tumors, or which of two men with identical prostate tumors, grows blood vessels aggressively and, therefore, should be treated more rapidly and vigorously.